Kindler Syndrome via the FERMT1 Gene

Kindler syndrome is the fourth major subtype of epidermolysis bullosa, which is characterized by congenital blistering, skin atrophy, photosensitivity, and skin fragility (Fine et al. 2008. PubMed ID: 18374450; Fine et al. 2014. PubMed ID: 24690439). Other features include palmoplantar keratoderma, gingival erosions, and ocular, esophageal, gastrointestinal and urogenital involvement. Patients with Kindler syndrome are also at risk to develop mucocutaneous malignancy (Lai-Cheong et al. 2010. PubMed ID: 19945624).

Kindler syndrome is an autosomal recessive disorder caused by variants in FERMT1. Kindlin-1 (fermitin family homologue 1), encoded by FERMT1, is a membrane-associated structural/signaling protein involved in integrin signaling and linking the actin cytoskeleton to the extracellular matrix. It is a key protein component for normal adhesion of keratinocytes to fibronectin and laminin. To date, more than 80 distinct pathogenic variants have been documented (Human Gene Mutation Database). The majority of the reported causative variants are nonsense variants (except for two missense variants). There have also been reports of small and gross deletions, insertions, duplications as well as splicing variants. Additionally, one Alu element insertion involving FERMT1 has been reported (Jobard et al. 2003. PubMed ID: 12668616; Has et al. 2011. PubMed ID: 21936020; Lai-Cheong et al. 2010. PubMed ID: 19945624; Youssefian et al. 2015. PubMed ID: 25599393; Vahidnezhad et al. 2017. PubMed ID: 28830826).

Ashton et al. found 17 different loss-of-function FERMT1 variants in 41 clinically diagnosed Kindler syndrome families (Ashton et al. 2004. PubMed ID: 14987263). Youssefian et al. identified FERMT1 pathogenic variants in 11 out of 13 families affected with Kindler syndrome (Youssefian et al. 2015. PubMed ID: 25599393).

This test provides full coverage of all coding exons of the FERMT1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).